Resorbable interbody spinal fusion devices

ABSTRACT

A resorbable interbody fusion device for use in spinal fixation is disclosed. The device is composed of 25–100% bioresorbable or resorbable material. The interbody fusion device of the invention can be in any convenient form, such as a wedge, screw or cage. Preferably, the resorbable device of the invention is in the shape of a tapered wedge or cone, which further desirably incorporates structural features such as serrations or threads better to anchor the device in the adjoining vertebrae. The preferred device further comprises a plurality of peripheral voids and more desirably a central void space therein, which may desirably be filled with a grafting material for facilitating bony development and/or spinal fusion, such as an autologous grafting material. As the preferred material from which the resorbable interbody fusion device is manufactured is most likely to be a polymer that can produce acidic products upon hydrolytic degradation, the device preferably further includes a neutralization compound, or buffer, in sufficiently high concentration to decrease the rate of pH change as the device degrades, in order to prevent sterile abscess formation caused by the accumulation of unbuffered acidic products in the area of the implant.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 09/131,716, filed Aug. 10, 1998 (now U.S. Pat. No.6,241,771), which claims priority to U.S. Provisional Application Nos.60/055,291, filed Aug. 13, 1997; 60/074,076, filed Feb. 9, 1998;60/074,197, filed Feb. 10, 1998, and 60/081,803, filed Apr. 15, 1998,the entire disclosures of which are incorporated herein by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not applicable

BACKGROUND OF THE INVENTION

The present invention relates to the field of interbody spinal fusiondevices.

In the structure of the spine of vertebrates including humans, the spacebetween adjacent vertebrae is referred to as the interbody space. Innormal spines, this space is occupied by the structure commonly referredto as a disc. This intervertebral structure separates and cushions thevertebrae.

Various pathologic and traumatic conditions require excision of a spinaldisc and stabilization of the superior and inferior vertebrae while bonyfusion develops. In 1995, approximately 225,000 new spinal fusions wereperformed in the United States alone, and of these about one half wereperformed in the thoracic and cervical spine, with the remaining spinalfusions focused on the lumbar spine. To stabilize the spine where thesurgery has occurred, an internal fixation device is frequently used.Such implants provide the ability to improve spinal alignment andmaintain the developing alignment while fusion develops. Fixation of thespine can further correct deformity and provide immediate stability,thereby facilitating spinal fusion, early mobilization, and, whennecessary, entry into rehabilitative programs.

The use of fixation devices is beneficial in several ways. First, theavoidance of long-term bed rest, thought by many to decreasenon-neurological morbidity, is achieved. Additionally, fixation devicesare thought to promote fracture healing and therefore reduce the needfor rigid and cumbersome post-operative bracing.

While a number of commercially available implants for spinalstabilization are known, these devices are not resorbable and therefore,remain permanently at the implant site. Meticulous bone preparation andgrafting is essential for successful long-term stability using currentdevices. Metallic and graphite implants have been known to fatigue andwill eventually fail if the desired solid bony fusion is not achieved.Thus, it would be advantageous to obtain successful bony fusion andspinal development while avoiding the use of devices having theaforementioned drawbacks.

SUMMARY OF THE INVENTION

The present invention is directed to resorbable interbody fusion devicesfor use as spacers in spinal fixation, wherein the device is composed of25–100% bioresorbable or resorbable material. The devices can be in anyconvenient form, such as a wedge, screw or cage. In one embodiment, theinterbody fusion device of the invention further desirably incorporatesstructural features such as serrations to better anchor the device inthe adjoining vertebrae. In another embodiment, the device comprises aplurality of peripheral voids and more desirably a central void spacetherein, which may desirably be filled with a grafting material forfacilitating bony development and/or spinal fusion, such as anautologous grafting material. In addition, void spaces increase thesurface area of the device, thereby providing multiple sites forresorption to occur.

In yet another embodiment, the interbody fusion device of the inventionfurther includes reinforcing fibers to enhance the structural propertiesthereof. These fibers may be made of the same polymeric material as theresorbable material from which the interbody fusion device is made, froma neutralization compound or, alternatively, from another biocompatiblepolymer, which may be crosslinked with a suitable crosslinking agent toyield an interpenetrating network for increased strength and stability.In another alternative embodiment, the reinforcing fibers areincorporated into the device, e.g., during the molding process, beingplaced in the mold under tension and released after the process ofmolding is complete.

Bioerodible polymers that are useful in the invention includepolydioxanone, poly(ε-caprolactone); polyanhydride; poly(ortho ester);copoly(ether-ester); polyamide; polylactone; poly(propylene fumarate)(H[—O—CH(CH₃)—CH₂—O—CO—CH═CH—CO—]_(n)OH); and combinations thereof. In apreferred embodiment, the polymer poly(lactide-co-glycolide) (PLGA: H[—OCHR—CO—]_(n)OH, R═H, CH₃), with a lactide to glycolide ratio in therange of 0:100% to 100:0% inclusive, is used.

As many of the preferred bioerodible polymers from which the resorbableinterbody fusion device is manufactured are polymers that can produceacidic products upon hydrolytic degradation, the device preferablyfurther includes a neutralization compound, or buffer. Theneutralization compound is included in sufficiently high concentrationto decrease the rate of pH change as the device degrades, in order toprevent sterile abscess formation caused by the accumulation ofunbuffered acidic products in the area of the implant. Most preferably,the buffering or neutralizing agent is selected from a group ofcompounds wherein the pKa of the conjugate acids of the buffering orneutralization compound is greater than the pKa of the acids produced byhydrolysis of the polymers from which the device is prepared.

The neutralization compound, or buffer, included in the bioerodiblematerial of the invention may be any base, base-containing material orbase-generating material that is capable of reacting with the acidicproducts generated upon hydrolysis of the bioerodible polymer. Polymericbuffers which preferably include basic groups which neutralize theacidic degradation products may also be used as buffering compounds.Another class of useful buffering compounds are those which, on exposureto water, hydrolyze to form a base as one reaction product.

In another alternative embodiment, the resorbable interbody fusiondevice of the invention preferably includes a biological growth factor,e.g., bone morphogenic protein, to enhance bone cell growth. To protectthe growth factor and to provide for controlled delivery, the biologicalgrowth factor may itself be compounded with a resorbable polymer in someof the many techniques available and prepared as a growth factor/polymercomposite in pellet form, in small particle form or within theinterstices or pores of a polymeric foam or low-density polymer and thispolymer/growth factor composite is deposited into void spaces of theresorbable spinal fusion device. Alternatively, the growth factor, orprotected growth factor, may simply be directly incorporated into thecomponent formulation of the resorbable spinal fusion device.

Active periosteum cells may also be incorporated into a foam, e.g.,deposited into void spaces of the resorbable spinal fusion device, inorder to facilitate bone cell fusion. Further, the resorbable spinalfusion device of the invention may be prepared in such a manner as toexhibit a piezoelectric effect, to enhance bone wound healing.

As used herein, the terms “resorbable” and “bioresorbable” are definedas the biologic elimination of the products of degradation by metabolismand/or excretion and the term “bioerodible” is defined as thesusceptibility of a biomaterial to degradation over time, usuallymonths. The terms “neutralization compound” or “buffer” are defined asany material that limits or moderates the rate of change of the pH inthe implant and its near environment upon exposure to acid or base. Theterm “acidic products” is defined herein as any product that generatesan aqueous solution with a pH less than 7.

DESCRIPTION OF THE DRAWINGS

The invention will be more fully understood from the following detaileddescription taken in conjunction with the accompanying drawings inwhich:

FIGS. 1A, 1B and 1C are perspective top, side and front views,respectively, of an interbody spinal fusion device according to thepresent invention;

FIGS. 2A, 2B and 2C are top, side and perspective views, respectively,of another embodiment of an interbody spinal fusion device of theinvention;

FIGS. 3A, 3B and 3C are top, side and perspective views, respectively,of another embodiment of an interbody spinal fusion device of theinvention;

FIGS. 4A and 4B are side and top views, respectively, of anotherembodiment of an interbody spinal fusion device of the invention;

FIGS. 5A and 5B are side and top views, respectively, of anotherembodiment of an interbody spinal fusion device of the invention;

FIG. 6A is a perspective view of a mold and ram assembly for preparingan interbody spinal fusion device of the invention;

FIGS. 6B and 6C are edge and plan views, respectively, of the front faceplate of the mold of FIG. 6A;

FIG. 6D shows a disc with serrated slots for use in the mold of FIG. 6A;

FIGS. 6E and 6F are front and side views, respectively, of a threadedtension tube used with the mold of FIG. 6A;

FIG. 6G is a section through a mold assembly fitted with reinforcingfibers and associated holder assemblies;

FIG. 7 is a plot of displacement versus load for an interbody spinalfusion device of the invention; and

FIG. 8 shows compression strength with load for interbody spinal fusiondevices of the invention with and without the incorporation of abuffering or neutralizing compound.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides, in one embodiment, an interbody spinalfusion device (IFD) comprising a resorbable spinal wedge for vertebralspacing as an adjunct to spinal fusion. Made from a biodegradable,biocompatible polymer, preferably poly(lactic-co-glycolic) acid (PLGA),discussed further below, this resorbable spacer incorporates peripheralvoids and central voids, which can be filled with autologous graftingmaterial to facilitate bony development and spinal fusion, and serratedor threaded faces to stabilize and align vertebral bodies. The spinalfusion device of the invention is used as an adjunct to fusions of thecervical, thoracic or lumbar vertebrae, the configuration and dimensionsof the device depending on the site of use.

A preferred embodiment of a spinal implant, fabricated from abiocompatible and biodegradable polyester and intended to replace acervical disc, C4, 5, or 6, is shown in FIGS. 1A, 1B and 1C. A rodmolded from a suitable material, as described below, is machined to thedesired configuration and dimensions. Relatively complex geometries canbe readily fabricated in this manner. Suitable biocompatible extraneousmaterials such as plasticizers or other machining aids, can be includedin the material if desired.

As shown in FIG. 1A, a preferred resorbable interbody spinal fusiondevice of the invention 10 is in the shape of a tapered wedge, having atop face 11, a bottom face 12, side faces 13, a front end 14 and a backend 15. The surfaces of top and bottom faces 11 and 12 each haveserrations 16 to aid in anchoring the device to the surrounding bone.Wedge 10 preferably contains holes 17 of convenient diameter, which maybe drilled through the wedge to facilitate resorption of the polymerfrom which the device has been made. A plurality of channels or ports 18through the wedge or a larger center hole 19 in the wedge are useful forthe introduction of autologous bone. As illustrated in FIGS. 1B and 1C,the spinal wedge is preferably machined to have a taper from back end 15to front end 14, such that the front end 14 is narrower than the backend 15.

In another embodiment, as shown in FIGS. 2A–2C resorbable spinal fusiondevice 20 is shaped like a tapered rod having ridges 22 with threads 21.Device 20 functions as a screw and contains a cylindrical axiallyextending hole 23 and slots 24 to facilitate screwing the device intothe spine of the patient. The device also contains recesses 26 betweenridges 22 to facilitate ingrowth of tissue that would aid in anchoringthe device in place.

As shown in FIGS. 3A–3C, in a further embodiment, the device 30 is ofcruciform shape having arms 33. Threads 31 extend the length of theouter surfaces of arms 33. In another embodiment, shown in FIGS. 4A–4B,the device is shaped like a threaded screw having a continuous thread 41provided around the surface of the tapered body. Cylindrical holes 43and 44 are provided through the body, the holes being orthogonal to eachother and to screw axis 42. A cylindrical hole 45 is provided coaxiallywith axis 42. Slots 46 in the top 48 serve to position and retain a toolthat can be used to screw the device into place.

As shown in FIGS. 5A and 5B, a further embodiment of a threaded screwcontains flat side areas 52 alternating with threaded corner areas 51.Slots 53 can be machined or otherwise provided in the flat areas, tofacilitate ingrowth of tissue, and can be of a constant width or can betapered. A slot 56 in top 58 of the device accommodates a suitable toolto facilitate insertion.

For replacement of one of the cervical discs C4, C5, or C6, the deviceshown in FIGS. 1A–1C preferably measures 15 mm laterally by 12 mmsagittally. The flattened side, positioned posterially, is 6–8 mm thick,enlarging to about 7–9 mm at the anterior edge; thus the device has ataper of approximately 4.8 degrees. Both surfaces are serrated, theserrations directed laterally. The serrations may be either square cutor cut at an angle with one face vertical and the other sloping upwardanteriorly.

The thickness of the device of the invention will govern the rate atwhich it degrades and total degradation time. Thus, interbody spinalfusion devices can be prepared with multiple thicknesses, but all havingthe same approximately 5° taper. For example, the anterior thicknesscould range from 7 to 9 mm and the posterior thickness from 6 to 8 mm.The taper provides the correct orientation to the vertebrae with whichthe device is in contact and can also serve to keep the device in place.

The vertebral body is a fairly cylindrical mass consisting of cancellousbone surrounded by a thin layer of cortical bone. Thus, the mechanicalproperties of the device should preferably match those of the cancellousbone of the vertebrae in regard to proportional limit stress,compression at proportional limit, modulus of elasticity, failure stressand compression at failure (See, e.g., Lindahl, Acta Orthop. Scand.47:11, 1976; Hansson et al., Spine 12:56, 1987).

Bioerodible polymers that are useful in the spinal fusion device of theinvention include polydioxanone, poly(E-caprolactone); polyanhydride;poly(ortho ester); copoly(ether-ester); polyamide; polylactone;poly(propylene fumarate)(H[—O—CH(CH₃)—CH₂—O—CO—CH═CH—CO—]_(n)OH);poly(lactic acid); poly(glycolyic acid); poly(lactide-co-glycolide); andcombinations thereof. Selection of a particular polymer is basedprimarily on the known properties of the polymer, such as thepotentiality for cross-linking, polymer strength and moduli, rate ofhydrolytic degradation, etc. One of ordinary skill in the art may takethese and/or other properties into account in selecting a particularpolymer for a particular application. Thus, the selection of aparticular polymer is within the skills of the ordinary skilledpractitioner.

In a preferred embodiment, the polymer poly(lactide-co-glycolide)(H[—OCHR—CO—]_(n)OH, R═H, CH₃) (PLGA) is used. The PLGA polymers usedaccording to the invention desirably have a lactide to glycolide ratioin the range of 0:100% to 100:0%, inclusive, i.e., the PLGA polymer canconsist of 100% L- or D,L-lactide (PLA), 100% glycolide (PGA), or anycombination of lactide and glycolide residues. These polymers have theproperty of degrading hydrolytically in vivo to form organic acids(lactic acid and glycolic acid) which accumulate in the regionsurrounding the implant. These acids are metabolized and eventuallyexcreted as carbon dioxide and water or enter the citric acid cycle.

The process by which alpha polyesters such as PLA, PGA, and PLGAbiodegrade is primarily by non-specific hydrolytic scission of the esterbonds. The L-lactic acid that is generated when PLA or PLGA degradesbecomes incorporated into the tricarboxylic acid cycle and is excretedfrom the lungs as carbon dioxide and water. Glycolic acid, produced bothby random hydrolytic scission and by enzymatically mediated hydrolysis,may be excreted in the urine and also can enter the TCA cycle andeventually be oxidized to carbon dioxide and water (Hollinger et al.,Clin. Orthop. Rel. Res. 207: 290–305, 1986).

A particularly preferred polymer for use in the device of the inventionis poly(d,l-lactide-co-glycolide)-85:15 (Boehringer-Ingelheim:distributor, Henley Chemicals, Inc., Montvale, N.J.), the 85:15designation referring to the lactide to glycolide mole ratio. Theparticularly preferred polymer is Resomer™ RG 858, with an inherentviscosity of approximately 1.4 corresponding to a weight averagemolecular weight of 232,000 as measured by gel permeation chromatography(GPC).

The polymer can be used as received or purified by precipitation fromtetrahydrofuran solution into isopropanol, air dried and thenexhaustively vacuum dried. Polymer data (composition and molecularweight) can be confirmed by nuclear magnetic resonance and by GPC (Hsuet al., J. Biomed. Mater. Res. 35:107–116, 1997).

Spinal fusions require interbody fusion devices that will maintainsignificant structural rigidity for 6–12 months. Strength requirementsdepend on the location of the disc to be replaced. When a person isstanding, the forces to which a disc is subjected are much greater thanthe weight of the portion of the body above it. Nachemson et al. (Acta.Orthop. Scand. 37:177, 1966; J. Bone Joint Surgery 46:1077, 1964; Clin.Orthop. 45:107, 1966) has determined that the force on a lumbar disc ina sitting position is more than three times the weight of the trunk.Daniels et al. (J. Appl. Biomater. 1:57–78, 1990) have reviewed much ofthe mechanical data of PGA, PLA, and PLGA.

As a bioerodible polymer undergoes hydrolysis in the body, any acidicdegradation products formed may be implicated in irritation,inflammation, and swelling (sterile abscess formation) in the treatedarea. To counteract this effect, a neutralization compound, or buffer,is desirably included in the bioerodible material to neutralize theacidic degradation products and thereby reduce the sterile abscessreaction, as described in copending U.S. application Ser. No.08/626,521, filed Apr. 3, 1996, the whole of which is herebyincorporated by reference herein.

The buffering compound included in the bioerodible material of theinvention may be any base, base-containing or base-generating materialthat is capable of reacting with the acidic products generated uponhydrolysis of the bioerodible polymer. Exemplary buffering materialsinclude salts of inorganic or organic acids, salts of polymeric organicacids or polymeric bases such as polyamines. Preferably calcium salts ofweak acids such as, e.g., tribasic calcium phosphate, dibasic calciumphosphate, or calcium carbonate are use. To be useful, the conjugateacids from which the buffering materials are derived must have a pKagreater than those of L-lactic acid (pKa=3.79), D, L-lactic acid(pKa=3.86), or glycolic acid (pKa=3.83), if a PLGA is the polymer whichis undergoing hydrolysis. Thus, for example, salts of acetic acid(pKa=4.74), or succinic acid (pK₁=4.19, pK₂=5.64) may also be used.

Buffer compositions of lower solubility are preferred because bufferloss from the polymer by diffusion will be slower (Gresser andSanderson, “Basis for Design of biodegradable Polymers for SustainedRelease of Biologically Active Agents” in Biopolymeric ControlledRelease Systems, Ch. 8, D. L. Wise, Ed., CRC Press, 1984). Preferably,the buffering compound has an acid dissociation constant that is smallerthan the acid dissociation constant of the acidic products generatedupon hydrolysis of the bioerodible polymer. Ionic buffers will, ingeneral, be the salts of weak acids. The acid, of which the buffer is asalt, should have an ionization constant (acid dissociation constant,K_(a)) which is less than the K_(a) for the acid products of polymerhydrolysis. Alternatively, the buffering compound has a hydrolysisconstant that is greater than the hydrolysis constant of the acidicproducts.

Hydroxyapatite (HA) and calcium carbonate (CC) were each investigated asbuffering fillers. Results demonstrate that the inclusion of CC or HA ina, e.g., PLGA fixture can effectively moderate the rate of pH decline asthe fixture degrades. Further, the rapid decline in pH can be offsetwithout considering 100% neutralization of the lactic and glycoliccomponents. Thus, even given that the polymeric fixture will be filledwith an inorganic buffer, the mechanical characteristics of the fixturecan be stabilized since the loading requirements for the buffer will notbe nearly as compromising as expected at the outset.

While both CC and HA can ameliorate the rate of decline in pH in theregion of polymer hydrolysis, the use of hydroxyapatite as a filler alsosupports osteoconductivity. Thus, HA not only promotes bony ingrowth andobviates loosening of the fixture, but also acts as a buffer therebypreventing the formation of sterile abscesses that have been attributedto the acidic degradative products of PLGA implants. The resultingresorbable fixture should be capable of a buffered hydrolyticdegradation and induction of bony ingrowth as resorption of the implantprogresses. A resorbable buffered bone fixture with such propertiescould provide structural support to stabilize and support a spinalrepair over the period of time required for natural healing to occur.

According to the invention a preferred buffering compound ishydroxyapatite. The formula Ca₁₀(OH)₂(PO₄)₆ may be written asCa(OH)₂.3Ca₃(PO₄)₂. When written in this manner it is seen that thefollowing neutralization reactions may be written:2RCO₂H+Ca(OH)₂.3Ca₃(PO₄)₂→2RCO₂ ⁻+Ca⁺²+2H₂O+3Ca₃(PO₄)₂12RCO₂H+3Ca₃(PO₄)₂→6H₂PO₄ ⁻+9Ca⁺²+12RCO₂ ⁻

The dissociation constant of water (the conjugate acid of the hydroxylion) is K_(w)=10⁻¹⁴. The basic phosphate ion, PO₄ ⁻³, can neutralize twoprotons forming the following acids, for which dissociation constantsare given:RCO₂H+PO₄ ⁻³→RCO₂ ⁻+HPO₄ ⁻²RCO₂H+HPO₄ ⁻²→RCO₂ ⁻+H₂PO₄K₂ of H₂PO₄ ⁻¹=6.2×10⁻⁸K₃ of HPO₄ ⁻²4.2×10⁻¹³

Buffers included in the polymer in solid form preferably have arelatively small particle size, for example, between less than 1.0 and250 μm. Particle size reduction can be accomplished by any standardmeans known in the art, such as ball milling, hammer milling, airmilling, etc. If buffer and polymer are to be blended by the dry mixingmethod (described below), the polymer particle size must also beconsidered. Polymers such as the PLGAs have relatively low glasstransition temperatures and melting temperatures. Thus, polymer particlesize reduction must be accompanied by cooling, for example using aTekmar A-10 mill with a cryogenic attachment.

Following milling, the desired particle size range of the buffer and thepolymer may be recovered by sieving through, for example, U.S. Standardsieves. Particles in the size ranges of <45, 45–90, 90–125, 125–180,180–250 μm may be conveniently isolated.

In selection of particle size range, it is sometimes desirable tocombine two or more ranges, or to use a wide range of sizes, forinstance all sizes less than 250 μm. Larger particles may be preferredin some applications of the invention because larger particles takelonger to be eroded by the acids and will therefore extend the usefullifetime of the buffer. In some cases particle size reduction will notbe necessary, such as when commercially available precipitated calciumcarbonate is used (e.g., Fisher Scientific, Inc., Catalog No. C-63).

The effectiveness of substances such as calcium carbonate andhydroxyapatite in neutralizing the acid products of polymer hydrolysisdepends not only on the quantity of the substance in the matrix, butalso on particle size and distribution, total surface area in contactwith the polymer, and solubility.

The presence of calcium ions in the buffered device has advantages withrespect to the physical properties of the device as it undergoeserosion. It has been shown that calcium ions form ionic bridges betweencarboxylate terminal polymer chains (Domb et al., J. Polymer Sci. A28,973–985 (1990); U.S. Pat. No. 4,888,413 to Domb). Calcium ion bridgesbetween carboxylate anions increase the strength of the composite inwhich the polymer chains are terminated by carboxylate anion end groupsover similar chains terminated by the hydroxyl groups of, e.g., terminalglycol moieties or terminal a-hydroxy acids. In an analogous manner, thepolyesters comprising the family of PLGA's are expected to bestrengthened by calcium bridges between carboxylate anion terminatedchains. As shown in FIG. 8 PLGA-85:15 wedges reinforced with 40% HAshowed an increase in compressive strength of approximately 5% over thenonreinforced controls.

Another class of useful buffering compounds are those which, on exposureto water, hydrolyze to form a base as one reaction product. Thegenerated base is free to neutralize the acidic products produced uponhydrolysis of the bioerodible polymer. Compounds of this type includearyl or alkyl carbamic acids and imines. These “basegeneratingcompounds” offer the advantage that the rate of hydrolysis of the basegenerator may be selected to correlate to the rate of hydrolysis of thebioerodible polymer.

Necessarily, the conjugate acid of the buffering compound has an aciddissociation constant that is smaller than the acid dissociationconstant of the acidic products generated upon hydrolysis of thebioerodible polymer. Alternatively, the buffering compound preferablyhas a hydrolysis constant that is greater than the hydrolysis constantof the acidic products.

Furthermore, the buffering compound preferably is only partially solublein an aqueous medium. In general, buffers of lower solubility arepreferred because buffer loss from the polymer by diffusion will beminimized (Gresser and Sanderson, supra). The quantity of buffer toinclude depends on the extent of neutralization desired. This may becalculated as shown below, using a PLGA of any composition buffered withcalcium carbonate as an example.

The average residue molecular weight, RMW, for a PLGA is given byRMW=14.03x+58.04where x=mole fraction of lactide in the PLGA. The term “residue” refersto the repeating lactide or glycolide moiety of the polymer. Forexample, if x=0.85 (PLGA=85:15), RMW=69.96. Thus, 1.0 gram of PLGA=85:15contains 0.01429 moles of residues which, on hydrolysis of the polymer,will yield 0.01429 moles of lactic and/or glycolic acid. If, e.g.,calcium carbonate is the buffering agent, and it is desired toneutralize, e.g., 50 mole % of the acids by the reactionCaCO₃+2HA→CaA₂+H₂O+CO₂where A=lactate or glycolate, then the weight of calcium carbonateneeded is (0.25) (0.01429) (100.09)=0.358 gram, and the required loadingis (0.358) (1+0.358) (100)=26.3% by weight.

Several methods may be used to incorporate the buffer into the polymer.These methods include solution casting coupled with solvent evaporation,dry mixing, incorporating the buffer into a polymer foam, and thepolymer melt method.

Solution casting coupled with solvent evaporation may be used withbuffers which are either soluble or insoluble in the solvent. Thebioerodible polymer is dissolved in any suitable volatile solvent, suchas acetone, tetrahydrofuran (THF), or methylene chloride. The buffer,which may be soluble or insoluble in this solvent, is added to give thefinal desired ratio of polymer to buffer. If particle size reduction ofthe buffer is necessary, it may be accomplished by ball milling thesuspension of buffer in the polymer solution. In contrast, if the bufferis soluble in the chosen solvent, particle size reduction at any stageis not necessary.

The suspension or co-solution is cast as a film on a glass or otherinert surface, and the solvent is removed by air drying. Residualsolvent remaining in the film may be further removed by subjecting thefilm to vacuum drying at elevated temperatures. As an example, ifcalcium carbonate is to be used as a buffering compound and it isdesired to neutralize 50% of the acid formed by hydrolysis ofPLGA-50:50, the buffer content of the composition should be 27.8%.

In an exemplary embodiment, to prepare 50 grams of composite, 36.1 gramsof PLGA-50:50 are dissolved in approximately 250 ml of tetrahydrofuran,and 13.9 grams of calcium carbonate of the desired particle size rangeis added to the solution mixture. After distributing the calciumcarbonate homogeneously by mixing, the suspension is dried to a film asdescribed above.

The resulting film may be processed by compaction under high pressure,extruded through a die, injection molded, or other method known in theart. Further definition of the final shape may be accomplished at thispoint by any desirable machining process, such as lathing.

In the dry-mixing method, a polymer of appropriate particle size rangeis mixed with the buffer, also of chosen particle size range, inproportions to give the desired stoichiometric buffering capacity. Thedry mixture is thoroughly blended by rotating the mixture in a ball milljar from which the grinding balls have been omitted, or other suitablemixing device. The blended mixture may then be processed by compaction,extrusion, injection molding, etc., as described above.

In the polymer melt method, a known weight of the buffer is incorporatedby mixing into a known weight of a suitable melted polymer. A quantityof polymer is heated to a temperature above its melting point, and asuitable buffer is blended into the melted polymer. The resultingpolymer/buffer composite is solidified by cooling, and may be processedas described above, or ground and sieved prior to processing.

In some applications, it may be desirable to protect the bufferingcompound, for example, during processing according to the melt method,or to make the buffering compound available at the later stages ofpolymer degradation. In such cases, it is desirable to coat thebuffering compound particles with a material that degrades at a slowerrate than the material chosen for the fixation devices. Thus, thebuffering compound is exposed only after the body of the device and thecoating material have partially degraded. Exemplary materials used tocoat the buffering compound particles include high molecular weightpoly(L-lactide) or poly(ε-caprolactone).

The particles of buffering compound may be coated with the protectivematerial by any method that coats particles, such as spray coating witha solution of protecting polymer or micro-encapsulation. Alternatively,a chosen protective polymer may be made in a melted state and bufferparticles are added. The melt is cooled and ground and milled to thedesired particle size range. Alternatively, the buffering compound maybe added to a solution of the protective polymer and removing thesolvent by evaporation. The dried mass is compacted in a mold under highpressure and grinding or milling the compacted mass to the appropriateparticle size range.

The resorbable spinal fusion device of the invention optionally includesa biological growth factor, e.g., bone morphogenic protein, to enhancebone cell growth. To protect the growth factor and to provide forcontrolled delivery, the biological growth factor may be itselfcompounded with a resorbable polymer by one of the many techniquesavailable and prepared as a growth factor/polymer composite in pelletform, in small particle form or within the interstices or pores of apolymeric foam or low-density polymer and this polymer/growth factorcomposite deposited into void spaces of the resorbable spinal fusiondevice. Alternatively, the growth factor may simply be directlyincorporated into the component formulation of the resorbable spinalfusion device.

Active periosteum cells, or other bony cells, may be also incorporatedinto a foam surrounding, or deposited in, the resorbable spinal fusiondevice so that the cells may facilitate bone cell fusion. To carry outsuch an incorporation, the periosteum surrounding a human bone isremoved and cultured following standard cell culturing techniques. Thescaffold for such periosteum cell growth is a resorbable polymer foam ormesh. This scaffolding is prepared by dipping the completed device in apolymer/solvent (such as PLGA dissolved in acetic acid). The so-wetteddevice is then frozen and subsequently freeze-dried (lyophilized)resulting in a foam layer (or coating) of polymer surrounding thedevice. After the periosteum cells have been grown in this foam layer,the device is incorporated into the spine for the enhancement of spinalfusion.

In another embodiment, the resorbable spinal fusion device may beprepared in such a manner as to exhibit a piezoelectric effect. It isknown that oriented (molecularly aligned) biopolymers such as PLGA havepiezoelectric characteristics. In addition, the oriented biopolymerpoly-l-lactic acid (PLLA) has been shown to promote bone wound healing(Shimono et al., In Vivo 10:471–476, 1996 and Ikada et al., J. Biomed,Mater. Res. 30:553–558, 1996). To take advantage of this phenomenon, theresorbable polymer is first aligned, by drawing, for example, such thatall polymer chains are essentially parallel. The spinal fusion device isthen cut from this aligned polymeric material such that the polymerchains are at approximately a 45° angle to the surface of the device,this angle being known to produce the optimal piezoelectric effect.Buffers, reinforcement materials, growth factors, etc., may also beincluded in processing of the spinal fusion device to exhibit thisphenomenon.

As described by White et al. (Clinical Biomechanics of the Spine, 2ndedition, 1990), there are four stages of maturation of the arthrodesis(spinal fusion): I, fibrous healing; II, mixed fibrous and osseoushealing; III, immature osseous healing; and IV mature osseous healing.Stage I requires maximum protection with restricted activity and perhapsa protective orthosis. During stage II relatively less protection isrequired although with restricted activity. During stage III the patientis allowed normal but nonvigorous activity. In stage IV, maximum healingwill be reached. For clinically stable patients the first three stagesrequire about six weeks each, and stage IV, a minimum of six weeks.Clinically unstable patients require more time, especially for the firsttwo stages. Thus the goals for duration and strength may be estimated.

A prototype device has been prepared for in vitro determination ofweight loss and failure strength as a function of time. Due to theasymmetric design of the IFD, it is not feasible to measure thecompressive modulus over time of the in vitro prototypes. Thisparameter, as well as failure and ultimate strength over time in vitro,has been measured on cylindrical discs of the same overall dimensions.In vitro experiments permit monitoring of the change in molecular weightin time for correlation with the mechanical measurements. Devices aretested for mechanical properties, e.g., compressive strength,compressive modulus, with equipment such as, e.g., the TA-XT2 TextureAnalyzer (Texture Technologies Corporation) or the Instron 8511Servo-Hydraulic System (Instrom Corp.).

PLGA-85:15 (Resomer RG 858) including reinforcing fibers and HA bufferwas molded at approximately 50° C. under a force of 7–9 tons to form atranslucent cylindrical rod 1.6 cm in diameter and 5.0 cm in length.Devices were then machined to the appropriate final dimensions, asdiscussed earlier. White and Panjabi (p. 29) report dimensions andstresses to which thoracic vertebrae are subject. The average area ofthe upper and lower end plates of T1 is about 340 mm², and is subject toa loading force of about 2000 N. The compressive strengths of exemplarybuffered and reinforced devices were, in all cases, greater than 13,000N. Thus, the initial strength of these PLGA-85:15 devices is in excessof the stress to which cervical vertebrae will be subject and greateralso than clinical targets of 10,000 N. Devices so made do not fractureat failure but rather irreversibly compress.

FIG. 7 illustrates this phenomenon. Failure at 13 kN is indicated by aslowly rising load at displacements greater than about 1.5 mm. If thetested device had failed by fracture, a rapid drop in load would haveresulted. The design of the IFD and the PLGA comonomer ratio (i.e.,lactide:glycolide ratio) enable the device to function through the fourstages of healing with progressive loss of mass and strength. Inclinically stable situations, at the end of stage I, the device shouldretain 70–80% of its mechanical strength, and at the end of stage II,50% of its strength should be retained. During stages III and IV,further slow degradation will occur with complete resorption by oneyear.

Prototype devices have been prepared for feasibility trials with goatsas the animal model. A viable model for testing fusion materials in thecervical spine is the in vivo goat model. Unlike most quadrupeds, thegoat holds its head erect, thus loading the cervical vertebrae in amanner similar to humans. Although there are geometric differences, therelative sizes of the disc and vertebral bodies are similar to those ofthe human. (Pintar et al., Spine 19:2524–2528, 1994; Zdeblick et al.,Spine 17(105):5418–5426, 1992.) The goat is thus the animal model ofchoice for testing the spinal fusion device of the invention.

The experimental procedure followed in the in vivo goat model is asfollows. Anesthetized animals undergo implantation via a surgery to theanterior cervical spine (Pintar et al., Spine 19:2524–2528, 1994). Afterexposing the lower 5 cervical segments, discectomy is performed at fourlevels. Two resorbable IFD's filled with cancellous bone are placed intwo of these spaces, the others receive a piece of tricortical iliacbone graft in place. The bone graft and cancellous bone are harvestedfrom the goat iliac crest through a separate incision over the hip bone.Placement of the IFD or the graft in upper or lower sites is alternatedfor each animal with an intact disc space between implants. Theoperative sites are closed, and the animals allowed to recover.

At sacrifice, the spinal column of the goat is excised leaving theintact ligamentous column. The cervical and lumbar sites are separatedand radiographed before mounting for biomechanical (as described above)or histological analyses for resorptive activity and new bone formation.The fusion rate and biomechanical stiffness are evaluated for spinalunits harvested from the goats. Spinal units undergo radiographicimaging to assess fusion, biomechanical testing to assess strength, andhistological analysis to assess tissue changes. The results are comparedto conventional graft-based spacers and fusion devices.

PLGA implants can be effectively reinforced by the use of degradablescaffolds which are molecularly dispersed in the host PLGA polymer. Forexample, a solid solution containing PLGA, poly(propylene fumarate)(PPF), and vinyl pyrrolidinone(VP) as a crosslinking agent (or othervinyl monomer) may be heated with an initiator (such as benzoylperoxide). The PPF chains are crosslinked by VP to form aninterpenetrating network of crosslinked PPF and PLGA polymer chains.Following heating, further crosslinking is possible using y-irradiation,e.g. 2.5 mrad.

Several reinforcement techniques described in the literature includeself-reinforcement using aligned PLGA fibers (Vainionpaa et al.,Biomaterial 8:46–48, 1987; Pihlajamaki et al., J. Bone and Joint Surgery74:13:853–857, 1992; Ashammakhi et al., J. Biomedical Materials Research29: 687–694, 1995) and reinforcement with calcium phosphate glass fibers(R. A. Casper et al., Polym. Mater. Sci. Eng. 53:497–501, 1985).

Reinforcement can also be achieved according to the invention by moldinga rod of rectangular or other suitable cross-section that containsfibers under tension using the mold and ram assembly of the invention,as shown in FIGS. 6A–6G. Referring to FIG. 6A, mold cavity 61 and ram 62are rectangular in cross-section in the illustrated embodiment. The moldillustrated is constructed of five plates (front face plate 63, rearface plate 64, side plates 65 and bottom plate 66), suitably fastened orbonded together. The front and rear face plates 63, 64 are machined orotherwise formatted, as will be described below, with key holes 60 toreceive holder assemblies for the reinforcing fibers, which comprisefront and rear tension tubes, front and rear tension tube caps, serrateddiscs, and a front tension tube threaded nut.

Referring to FIG. 6B (an edge view of front face plate 63) and FIG. 6C(a plan view of front face plate 63), the inside face 67 of plate 63contains a circular recess 68, with associated slots 69. Recess 68adjoins a larger recess 70 that extends to the outside face 71 of frontface plate 63. Recess 70 includes associated slots 72. The axis betweenslots 72 is perpendicular to the axis between slots 69. A smallerdiameter recess stop 73 separates recess 68 from recess 70. Rear faceplate 64 is similarly configured.

Referring now also to FIGS. 6D–G, the mold is assembled for use asfollows. A disc 75 (FIG. 6D) having serrated slots 76 is threaded withpolymer fibers 88, which are distributed throughout the serrated slots.The distribution of the fibers is spatially maintained by theserrations. Referring also to FIG. 6G, discs 75 with fibers in place aremounted in recesses 68 in the front and rear face plates 63, 64 of theassembled mold. Orientation of discs 75 is maintained by vanes 77 on thesides of the discs, which fit into slots 69. Alternatively, discs 75 maybe mounted first in face plates 63, 64 and threaded in place. Theprotruding fiber bundles are then threaded through front and reartension tube assemblies 78, 79, which are positioned in recesses 70 inthe front and rear face plates 63, 64, respectively. Tension tubeassemblies 78, 79 consist of tension tubes 80, each having vanes 82which fit into slots 72 in the front and rear face plate recesses 70,respectively, thus maintaining the orientation of the tubes. The tensiontubes are closed with caps 83 to complete assemblies 78, 79. The fiberbundles are threaded additionally through holes 84 in the front and reartension tube caps, as they exit the tension tubes. Holes 84 areoff-center and below the axis of the tension tubes. This configurationholds the fibers against the serrations of the discs. Outside the caps,the fibers may be knotted to keep them from slipping back through theholes. Other methods of anchoring the fibers may be used. For example, abead of cement (such as epoxy or cyanoacrylate adhesives) may be builtup on the outside of the caps to keep the fibers from slipping through.Also referring to FIGS. 6E and 6F, it can be seen that the tension tube80 of front tension tube assembly 78 is exteriorly threaded 85 along itslength and equipped with a nut 86 which, when tightened against the faceplate, pulls the tension tube partially out of the face plate, thusputting the fibers under tension.

To prepare a reinforced resorbable spinal fusion device, mold cavity 61of the assembled mold is then filled with the appropriate powderedformulation. The powdered formulation may be evenly distributed amongthe fibers by placing the mold on a vibrator. Ram 62 is put in place, inthe opening of the mold, and pressure is exerted. The mold may be heatedexternally with heating tapes, or it may be so machined as to haverecesses for cartridge heaters. When the molding process is complete,the tension on the reinforcing fibers is released, and the completeddevice is removed from the mold.

While the present invention has been described in conjunction with apreferred embodiment, one of ordinary skill, after reading the foregoingspecification, will be able to effect various changes, substitutions ofequivalents, and other alterations to the compositions and methods setforth herein. It is therefore intended that the protection granted byLetters Patent hereon be limited only by the definitions contained inthe appended claims and equivalents thereof.

1. A resorbable interbody spinal fusion device for spinal fixation, saiddevice comprising an interbody spinal fusion device comprising (1)between 25 and 100% of a biocompatible, bioerodible polymer whichproduces acidic products or low molecular weight resorbable fragmentsupon hydrolytic degradation, wherein the polymer includes astrengthening material selected from the group consisting of crosslinkedmonomers, reinforcing fibers, self-reinforcing aligned fibers of thepolymer, degradable polymeric scaffolds, and interpenetrating networks,(2) one or more void spaces, and (3) a buffering or neutralizing agent,wherein one or more of the void spaces comprises a grafting material forfacilitating bony development or spinal fusion.
 2. The resorbableinterbody spinal fusion device of claim 1, wherein said graftingmaterial is an autologous grafting material.
 3. The resorbable interbodyspinal fusion device of claim 1, wherein said device is shapedsubstantially as a tapered wedge or cone.
 4. The resorbable interbodyspinal fusion device of claim 1, wherein said device is shapedsubstantially as a threaded screw.
 5. The resorbable interbody spinalfusion device of claim 1, wherein said device is shaped substantially asa threaded rod of cruciform configuration.
 6. The resorbable interbodyspinal fusion device of claim 3, the device further comprising at leastone serrated or threaded outer face.
 7. The resorbable interbody spinalfusion device of claim 1, wherein said polymer or strengthening materialis selected from the group consisting of polydioxanone,poly(ε-caprolactone), polyanhydride, polyester, copoly(ether-ester),polyamide, polylactone, poly(propylene fumarate), and combinationsthereof.
 8. The resorbable interbody spinal fusion device of claim 7,wherein said bioerodible polymer is poly(lactide-co-glycolide) with alactide to glycolide ratio in the range of 0:100% to 100:0% inclusive.9. The resorbable interbody spinal fusion device of claim 1, whereinsaid buffering or neutralizing agent is a polymer comprising at leastone basic group.
 10. The resorbable interbody spinal fusion device ofclaim 9, wherein the basic group is selected from the group consistingof polyamines, polyesters, vinyl polymers, and copolymers of acrylicacid.
 11. The resorbable interbody spinal fusion device of claim 1,wherein said buffering or neutralizing agent is a compound that, onexposure to water, hydrolyzes to form a base.
 12. The resorbableinterbody spinal fusion device of claim 1, wherein said buffering orneutralizing agent is selected from the group consisting of carbonates,phosphates, acetates, succinates and citrates.
 13. The resorbableinterbody spinal fusion device of claim 1 wherein said strengtheningmaterial includes reinforcing fibers.
 14. The resorbable interbodyspinal fusion device of claim 13, wherein said reinforcing fibers aremade of said a bioerodible polymer.
 15. The resorbable interbody spinalfusion device of claim 13, wherein said reinforcing fibers are made ofsaid buffering or neutralizing agent.
 16. The resorbable interbodyspinal fusion device of claim 1, wherein said buffering or neutralizingagent is selected from the group consisting of compounds wherein the pKaof the conjugate acids of said compounds is greater than the pKa ofacids produced by hydrolysis of the polymer.
 17. The resorbableinterbody spinal fusion device of claim 1, wherein said device isfabricated from at least two bioerodible polymers.
 18. The resorbableinterbody spinal fusion device of claim 17, wherein one of said polymersis poly (propylene fumarate) which acts as a reinforcing material. 19.The resorbable interbody spinal fusion device of claim 17, wherein oneof said polymers has been cross-linked in the presence of a crosslinkingagent and an initiator, whereby said crosslinked polymer forms areinforcing interpenetrating network.
 20. The resorbable interbodyspinal fusion device of claim 17, wherein one of said at least twopolymers has been cross-linked in the presence of vinyl pyrrolidone as acrosslinking agent and an initiator.
 21. The resorbable interbody spinalfusion device of claim 17, wherein one of said at least two polymers hasbeen cross-linked in the presence of a crosslinking agent and benzoylperoxide as an initiator.
 22. The resorbable interbody spinal fusiondevice of claim 1, wherein said device is fabricated from a polymerwherein molecular chains of said polymer have been aligned to beessentially parallel.
 23. The resorbable interbody spinal fusion deviceof claim 22, wherein said device lass been cut such that the alignedpolymer molecular chains are at approximately a 45° angle to a surfaceof said device.
 24. The resorbable interbody spinal fusion device forspinal fixation of claim 1, wherein said buffering or neutralizing agentis hydroxyapatite.